The continued emergence of bacterial strains that are resistant to multiple broad classes of antibiotics has raised significant concern among the medical community, some even suggesting we may be about to enter a post-antibiotic era. Among resistant bacteria, carbapenemase-producing members of the Enterobacteriaceae, particularly Klebsiella pneumoniae carrying the blaKPC allele, are agents of major concern. Bacteriophages, viruses that infect bacteria, have been proposed as biological control agents for the treatment of these MDR bacterial infections. Phages have the advantages of being specific, non-toxic and capable of growing at the site of the bacterial infection, and have been shown to cure a wide variety of bacterial infections in animal model studies. However, little is understood regarding the principles of in vivo phage efficacy. The work proposed in this project will assemble a well-characterized library of lytic phages capable of killing KPC+ K. pneumoniae isolates, and develop mouse and rabbit models of asymptomatic KPC+ K. pneumoniae carriage and gut-derived bacteremia caused by KPC+ K. pneumoniae. The host ranges, resistance profiles, growth characteristics and in vivo performance of the phages in the library will be used to assemble a mixture of phages with maximal efficacy against a broad swath of clinically relevant KPC+ K. pneumoniae strains, and these will be evaluated in mouse and rabbit models of infection developed for this study. This work will produce a phage-based therapeutic that will have a direct application for treatment of KPC+ K. pneumoniae infection in humans, and will determine some of the phage parameters associated with in vivo efficacy.